Method for making a porous calcium phosphate article

ABSTRACT

The present invention discloses a method for making a porous calcium phosphate article including i) preparing a shaped article from a paste containing a calcium phosphate cement, a pore-forming powder and a setting liquid; ii) immersing the shaped article in an immersing liquid for a period of time so that the pore-forming powder is dissolved in the immersing liquid, creating pores in said shaped article; and iii) removing the resulting porous shaped article from the immersing liquid, wherein the resulting porous shaped article has an improved compressive strength. The porous shaped calcium phosphate article of the present invention may be used as a tissue-engineered scaffold, medical implant or a reinforcing constituent of a composite.

PRIORITY CLAIM

This application is a continuation of co-pending U.S. patent applicationSer. No. 10/780,728 entitled “METHOD FOR MAKING A POROUS CALCIUMPHOSPHATE ARTICLE” filed on Feb. 19, 2004, herein incorporated byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is related to a porous calcium phosphate articlefor use as a medical implant, and in particular to a method of making aporous calcium phosphate scaffold for use as tissue-engineered scaffold.

2. Description of the Related Art

A tissue-engineered scaffold (majority made from biodegradable polymers)has a very porous structure that allows living cells (usually taken fromthe patient being treated) to penetrate into the structure and be“seeded” in-vitro during a cell culture process. After a period of time(days or weeks) of cell culture, the cell-seeded scaffold is implantedinto either an animal (e.g., rat) whose immune system has been removed,or into the patient himself (usually under the skin for easier later-onprocess). During this period of time (weeks to months) the cells quicklymultiply from absorbing nutrients from the animal or the patient's body,and, at the same time, the scaffold itself is gradually dissolved orresorbed. When this process is substantially “mature”, the implant (nowa real bone) is removed from under the skin of the animal or the patientand re-implanted into the (wounded or diseased) site being treated. Thefollowing are some references describing some details about thebackground, requirements, applications, etc. of tissue-engineeredscaffold: U.S. Pat. No. 6,139,578; U.S. Pat. No. 6,200,606; U.S. Pat.No. 5,306,303; and U.S. Pat. No. 6,132,463.

It is advantageous if a tissue-engineered scaffold is bioresorbable,sufficiently porous and supportive at the same time. The conventionalhigh temperature (usually >1000° C.)-sintered porous hydroxyapatite (HA)block material does not possess sufficient micro/nano-sized porosity andis hardly bioresorbable. On the other hand, the conventionalbiodegradable polymer for scaffold application exhibits a relatively lowstrength and too high a dissolution rate.

SUMMARY OF THE INVENTION

A primary objective of the invention is to provide a porous calciumphosphate article or block for use as a tissue-engineered scaffold,which is free from the aforesaid drawbacks in the prior art, or as afunctional implant other than the tissue-engineered scaffold.

This objective is accomplished by providing a novel method for making aporous calcium phosphate article, which involves a) preparing a shapedarticle from a paste comprising a calcium phosphate cement, apore-forming powder and a setting liquid; and b) immersing said shapedarticle in an immersing liquid for a period of time so that saidpore-forming powder is dissolved in the immersing liquid, creating poresin said shaped article.

Features and advantages of the present invention are as follows:

-   -   1. The porous calcium phosphate article made according to the        present invention can transform into an apatite-dominated        material shortly after immersion in physiological solution or        after implantation.    -   2. The porous calcium phosphate block made according to the        present invention exhibits a higher strength than most other        bioactive or biodegradable porous blocks with a similar porosity        level.    -   3. The calcium phosphate block made according to the present        invention possesses a significant amount of micro- and        nano-sized porosity, that improves bioresorbability thereof.

DETAILED DESCRIPTION OF THE INVENTION

The preferred embodiments of the present invention include (but notlimited thereto):

1. A method for making a porous calcium phosphate article comprising:

-   -   i) preparing a shaped article from a paste comprising a calcium        phosphate cement, a pore-forming powder and a setting liquid;    -   ii) ii) immersing said shaped article in an immersing liquid for        a first period of time so that said pore-forming powder is        dissolved in the immersing liquid, creating pores in said shaped        article;    -   iii) removing the resulting porous shaped article from said        immersing liquid; and    -   iv) immersing the porous shaped article from step iii) in an        impregnating liquid for a second period of time so that a        compressive strength of the resulting article removed from the        impregnating liquid is increased compared to that of said porous        shaped article without said impregnating treatment,    -   v) wherein step iii) is omitted and a compressive strength of        the resulting porous shaped article removed from the immersing        liquid after the first and the second periods of time is        increased compared to that of the resulting porous shaped        article removed after the first period of time, when the        immersing liquid and the impregnating liquid are the same.

2. The method according to item 1, wherein said pore-forming powder isselected from the group consisting of LiCl, KCl, NaCl, MgCl₂, CaCl₂,NaIO₃, KINa₃, PO₄, K₃PO₄, Na₂CO₃, amino acid-sodium salt, aminoacid-potassium salt, glucose, polysaccharide, fatty acid-sodium salt,fatty acid-potassium salt, potassium bitartrate (KHC₄H₄O₆), potassiumcarbonate, potassium gluconate (KC₆H₁₁O₇), potassium-sodium tartrate(KNaC₄H₄O₆.4H₂O), potassium sulfate (K₂SO₄), sodium sulfate, and sodiumlactate.

3. The method according to item 1, wherein the immersing liquid is anacidic aqueous solution, a basic aqueous solution, a physiologicalsolution, an organic solvent, or a substantially pure water.

3. The method according to item 3, wherein the immersing liquidcomprises at least one of Ca and P sources.

5. The method according to item 3, wherein the immersing liquid is aHanks' solution, a HCl aqueous solution or an aqueous solution of(NH₄)₂HPO₄.

6. The method according to item 3, wherein the immersing liquid and theimpregnating liquid are the same.

7. The method according to item 4, wherein the immersing liquid and theimpregnating liquid are the same.

8. The method according to item 5, wherein the immersing liquid and theimpregnating liquid are the same.

9. The method according to item 1, wherein the immersing liquid and theimpregnating liquid are different.

10. The method according to item 9, wherein the impregnating liquid isan acidic solution, a basic solution, a physiological solution, or asubstantially pure water.

11. The method according to item 10, wherein the impregnating liquidcomprises at least one of Ca and P sources.

12. The method according to item 10, wherein the impregnating liquid isa Hanks' solution, a HCl aqueous solution or an aqueous solution of(NH₄)₂HPO₄.

13. The method according to item 1, wherein the first period of time islonger than 10 minutes.

14. The method according to item 13, wherein the first period of time islonger than 1 day.

15. The method according to item 1, wherein the second period of time islonger than 10 minutes.

16. The method according to item 15, wherein the second period of timeis longer than 1 day.

17. The method according to item 1, wherein the immersing in step ii)and iv) is carried out at room temperature or at a temperature betweenabout 30 and 90° C.

18. The method according to item 1, wherein said preparing of step i)comprises the following steps:

-   -   (a) preparing a first powder as said calcium phosphate cement        comprising at least one Ca source and at least one P source, or        at least one calcium phosphate source;    -   (b) mixing said first powder and the pore-forming powder with        said setting liquid to form said paste, wherein said first        powder and said setting liquid undergo a hardening reaction;    -   (c) molding said paste into an article in a mold of a desired        shape and size before said hardening reaction is complete; and    -   (d) removing said molded article from said mold.

19. The method according to item 18, wherein said calcium phosphatesource in step (a) comprises one or more calcium phosphates selectedfrom the group consisting of alpha-tricalcium phosphate (α-TCP),beta-tricalcium phosphate (β-TCP), tetracalcium phosphate (TTCP),monocalcium phosphate monohydrate (MCPM), monocalcium phosphateanhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalciumphosphate anhydrous (DCPA), octacalcium phosphate (OCP), calciumdihydrogen phosphate, calcium dihydrogen phosphate hydrate, acid calciumpyrophosphate, anhydrous calcium hydrogen phosphate, calcium hydrogenphosphate hydrate, calcium pyrophosphate, calcium triphosphate, calciumphosphate tribasic, calcium polyphosphate, calcium metaphosphate,anhydrous tricalcium phosphate, tricalcium phosphate hydrate, andamorphous calcium phosphate.

20. The method according to item 19, wherein said calcium phosphatesource in step (a) is tetracalcium phosphate (TTCP).

21. The method according to item 19, wherein the calcium phosphatesource comprises at least one calcium phosphate particle having calciumphosphate whiskers on the surface of said calcium phosphate particle,wherein said calcium phosphate whiskers have a length of about 1-5000 nmand a width of about 1-500 nm.

22. The method according to item 19, wherein the setting liquid in step(b) is an acidic solution, a basic solution, or substantially purewater.

23. The method according to item 22, wherein said acidic solution isselected from the group consisting of nitric acid (HNO₃), hydrochloricacid (HCl), phosphoric acid (H₃PO₄), carbonic acid (H₂CO₃), sodiumdihydrogen phosphate (NaH₂PO₄), sodium dihydrogen phosphate monohydrate(NaH₂PO₄.H₂O), sodium dihydrogen phosphate dihydrate, sodium dihydrogenphosphate dehydrate, potassium dihydrogen phosphate (KH₂PO₄), ammoniumdihydrogen.phosphate (NH₄H₂PO₄), malic acid, acetic acid, lactic acid,citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid,oxalic acid and their mixture.

24. The method according to item 22, wherein said basic solution isselected from the group consisting of ammonia, ammonium hydroxide,alkali metal hydroxide, alkali earth hydroxide, disodium hydrogenphosphate (Na₂HPO₄), disodium hydrogen phosphate dodecahydrate, disodiumhydrogen phosphate heptahydrate, sodium phosphate dodecahydrate(Na₃PO₄.12H₂O), dipotassium hydrogen phosphate (K₂HPO₄), potassiumhydrogen phosphate trihydrate (K₂HPO₄.3H₂O), potassium phosphatetribasic (K₃PO₄), diammonium hydrogen phosphate ((NH₄)₂HPO₄), ammoniumphosphate trihydrate ((NH₄)₃PO₄.3H₂O), sodium hydrogen carbonate(NaHCO₃), sodium carbonate Na₂CO₃, and their mixture.

25. The method according to item 18, wherein step (c) further comprisesremoving a portion of liquid from said paste, so that a liquid/powderratio of said paste decreases.

26. The method according to item 18, wherein step (c) further comprisespressurizing said paste in said mold before said hardening reaction iscomplete to remove a portion of liquid from said paste, so that aliquid/powder ratio of said paste decreases.

27. The method according to item 26, wherein said pressuring is about 1to 500 MPa.

28. The method according to item 26, wherein step (c) further comprisesheating said paste during said pressurizing.

29. The method according to item 18, wherein step (c) further comprisesheating said paste during molding.

30. The method according to item 1 further comprising removing theresulting porous shaped article having an increased compressive strengthfrom said impregnating liquid; and cleaning and drying said porousshaped article after removed from said impregnating liquid.

31. The method according to item 30 further comprising heating theresulting cleaned and dried porous shaped article.

32. The method according to item 31, wherein said heating is conductedat a temperature between 50 and 500° C.

33. The method according to item 1, wherein said paste in step i)further comprises living cells.

34. The method according to item 1, wherein said immersing liquid instep ii) comprises living cells.

35. The method according to item 1, wherein said impregnating liquid instep iv) comprises living cells.

36. The method according to item 1, wherein said porous shaped articlehaving an increased compressive strength removed from said impregnatingliquid in step iv) has a porosity of at least 30 vol %.

37. The method according to item 1, wherein said porous shaped articlehaving an increased compressive strength removed from said impregnatingliquid in step iv) has a porosity of 50-90 vol %.

The porous shaped calcium phosphate article made according to the methodof the present invention may be used as a tissue-engineered scaffold,medical implant or a reinforcing constituent of a composite.

The following examples are intended to demonstrate the invention morefully without acting as a limitation upon its scope, since numerousmodifications and variations will be apparent to those skilled in thisart.

PREPARATIVE EXAMPLE 1 Preparation of TTCP Powder

A Ca₄(PO₄)₂O (TTCP) powder was prepared by mixing Ca₂P₂O₇ powder withCaCO₃ powder uniformly in ethanol for 24 hours followed by heating todry. The mixing ratio of Ca₂P₂O₇ powder to CaCO₃ powder was 1:1.27(weight ratio) and the powder mixture was heated to 1400° C. to allowtwo powders to react to form TTCP.

PREPARATIVE EXAMPLE 2 Preparation of Non-Dispersive TTCP/DCPA-Based CPCPowder (Abbreviated as ND-CPC)

The TTCP powder prepared according to the method of PREPARATIVE EXAMPLE1 was sieved and blended with dried CaHPO₄ (DCPA) powder in a ball millfor 12 hours. The blending ratio of the TTCP powder to the DCPA powderwas 1:1 (molar ratio). The resultant powder mixture was added to a 25 mMdiluted solution of phosphate to obtain a powder/solution mixture havinga concentration of 3 g powder mixture per 1 ml solution while stirring.The resulting powder/solution mixture was formed into pellets, and thepellets were heated in an oven at 50° C. for 10 minutes. The pelletswere then uniformly ground in a mechanical mill for 20 minutes to obtainthe non-dispersive TTCP/DCPA-based CPC powder (ND-CPC). The particles ofthis ND-CPC powder have whiskers on the surfaces thereof.

EXAMPLE 1 Effect of KCl Content and Immersion Time on CompressiveStrength of Porous CPC Block

To a setting solution of 1M phosphoric acid solution (pH=5.89) theND-CPC powder from PREPARATIVE EXAMPLE 2 was added in a liquid/powderratio (L/P ratio) of 0.4, i.e. 4 ml liquid/10 g powder, while stirring.KCl powder in a predetermined amount was mixed to the resulting mixtureby stirring intensively. The resulting paste was filled into acylindrical steel mold having a length of 12 mm and a diameter of 6 mm,and was compressed with a gradually increased pressure until a maximumpressure of 3.5 MPa was reached. The maximum pressure was maintained forone minute, and then the compressed CPC block was removed from the mold.At the 15^(th) minute following the mixing of the liquid and powders,the compressed CPC block was immersed in a deionized water at 37° C. for4 day, 8 days, and 16 days. The compressive strength of the specimens ofthe three different periods of immersion time was measured by using aAGS-500D mechanical tester (Shimadzu Co., Ltd., Kyoto, Japan) after thespecimens were dry. The measured dry specimen compressive strength islisted Table 1. TABLE 1 KCl/CPC Dry compressive strength (MPa) ratio byImmersion time (Day) weight 4 day 8 days 16 days 1 7.0 5.4 6.6 1.5 3.92.7 4.3 2 1.3 2.3 2.6

It can seen from Table 1 that the dry compressive strength of the porousCPC blocks decreases as the KCl/CPC ratio by weight increases.

EXAMPLE 2 Effect of KCl Content on Compressive Strength and Porosity ofPorous CPC Block

The procedures of EXAMPLE 1 were repeated except that the immersion timewas set at four days, and more KCl/CPC ratios by weight were chosen. Theresults are listed in Table 2. TABLE 2 KCl/CPC ratio Dry compressive byweight strength (MPa) Porosity (vol %)* 1 8.0 66.8 1.25 5.0 69.7 1.5 3.972.2 1.75 2.9 74.4 2 1.3 76.5 3 0.4 81.9*Porosity (vol %) was measured by Archimedes' method, and calculated asin ASTM C830.

The results in Table 2 show that the porosity of the porous CPC blockbecomes greater as the KCl/CPC ratio by weight increases. Morphology ofthe porous CPC blocks prepared in this example with the KCl/CPC ratiosby weight of 1.25, 1.5, 1.75 and 2.0 shows macro and micro-pores, whichwere observed with SEM.

EXAMPLE 3 Effect of KCl Content and Heat Treatment on Dry CompressiveStrength of Porous CPC Block

The procedures of EXAMPLE 1 were repeated except that the immersing timewas set at 4 days and the resulting porous CPC block was heat treated.The heat treatment included placing the porous CPC block in an oven at50° C. for 1 day; and then heating the dried porous CPC block in afurnace at the temperature and for a period of time set in Table 3 witha heating rate of 10° C./min. The compressive strength was measuredafter cooling of the heated CPC block. The conditions and results arelisted in Table 3. TABLE 3 KCl/CPC ratio Heat treatment Dry compressiveby weight conditions strength (MPa) 1 No 7 350° C., 1 hr 8.5  350° C., 2hrs 9.6 1.5 No 3.9 400° C., 2 hr 4.6

The data in Table 3 show that the heat treatment can enhance the drycompressive strength of the porous CPC block.

EXAMPLE 4 Effect of Molding Pressure and Immersing Liquid on DryCompressive Strength of Porous CPC Block

The procedures of EXAMPLE 1 were repeated except that the maximumpressure used to compress the paste in the mold was changed from 3.5 MPato the values listed in Table 4 and the immersion conditions were alsochanged as indicated in Table 4. Further, the KCl/CPC ratio by weightwas set at 2. The conditions and results are listed in Table 4. TABLE 4Mold Dry compressive pressure Immersion conditions strength (MPa) 3.5MPa 37° C. Deionized water, 4 days 1.3 50 MPa 37° C. Deionized water, 4days 4.7 156 MPa 37° C. Hanks' solution, 1 day; 5 37° C. deionizedwater, 3 days 156 MPa 37° C. Deionized water, 1 day; 4.2 37° C. Hanks'solution 3 days 156 MPa 37° C. Hanks' solution, 8 days 6 167 MPa 90° C.deionized water, 5 hrs 2.7 167 MPa 90° C. deionized water, 5 hrs; 3.7Hank.s solution 4 days

The data in Table 4 reveal that the dry compressive strength of theporous CPC block increases as the pressure used to compress the paste inthe mold increases.

EXAMPLE 5 Porosity and Compressive Strength of Porous CPC BlocksPrepared From Different Pore-Forming Powders

The procedures of EXAMPLE 1 were repeated by using sugar, KI,C₁₇H₃₃COONa and C₁₃H₂₇COOH instead of KCl. The immersion time was 14days in deionized water. In the cases where the C₁₇H₃₃COONa andC₁₃H₂₇COOH were used, the CPC blocks were further immersed in ethanolfor additional four days. The conditions and the results are listed inTable 4. TABLE 5 Pore-forming powder S^(a)) C.S. (MPa)^(b)) Porosity(vol %)^(c)) Sugar 1 4.1 58.4 KI 2 4.3 62.2 KI 3 1.7 75.5 C17H33COONa 18.0 56.0 C13H27COOH 2 5.9 60.1^(a))S = Pore-forming powder/CPC by volume.^(b))C.S. = dry compressive strength (hereinafter abbreviated as C.S.).^(c))Porosity: defined as in Table 2 (hereinafter the same definitionwill be used unless otherwise indicated).

It can be seen from Table 5 that various powders which are soluble inwater can be used in the preparation of a porous CPC block according tothe method of the present invention.

EXAMPLE 6 Effect of Immersion Solution and Immersion Temperature on C.S.and Porosity

In this example various immersing liquids at different temperatures wereused to prepare porous CPC blocks by repeating the procedures in EXAMPLE1, wherein the immersion time was set at 14 days, KI was used to replaceKCl, and KI/CPC ratio by volume was set at 3. The conditions and resultsare listed in Table 6. TABLE 6 Immersion immersion solution temperature(° C.) C.S. Porosity % deionized water 37 1.76 75.5 deionized water 252.2 — Ca(OH)₂ (0.03 M) 37 2.06 74.7 NaOH (0.03 M) 37 2.14 75.1 CaCl₂(0.03 M) 37 2.03 75.2 NaOH (0.03 M) 25 2.54 73.1

It can been seen from Table 6 that various aqueous solutions which areable to dissolve the pore-forming powder can be used in the preparationof a porous CPC block according to the method of the present invention.

EXAMPLE 7 Effect of Heat Treatment on C.S. and Porosity

The procedures of EXAMPLE 1 were repeated except that the immersion timewas set at 14 days, KI was used to replace KCl, and KI/CPC ratio byvolume was set at 3. Further the porous CPC block removed from theimmersing liquid (deionized water at 37° C.) was dried in an oven andthen subjected to a heat treatment at 100-800° C. for a period of 2-10hours in high temperature furnace with a heating rate of 10° C./min. Theconditions and results are listed in Table 7. TABLE 7 Heat treatmentcondition C.S. (MPa) No 1.7 100° C. - 2 hr 1.7 200° C. - 2 hr 2.4 400°C. - 2 hr 2.7 600° C. - 2 hr 1.5 800° C. - 2 hr 1.4 400° C. - 10 hr 2.2800° C. - 10 hr 1.4

As shown in Table 7 the optimal conditions for the heat treatment is400° C. for two hours, thereby the dry compressive strength of theporous CPC block was increased from 1.7 to 2.7 MPa.

EXAMPLE 8 Effect of NaCl Content and Immersion Temperature on C.S. andPorosity

The procedures of EXAMPLE 1 were repeated except that NaCl was used toreplace KCl, and NaCl/CPC ratio by weight was set in Table 8. Furtherthe paste was immersed in the immersing liquid (deionized water at 37°C. and 60° C.) for 7 days. The conditions and results are listed inTable 8. TABLE 8 Dry compressive strength (MPa) NaCl/CPC ratio Immersiontemperatue (° C.) by weight 37 60 0 75.5 58.2 0.25 28.8 27.9 0.5 11.210.4 0.75 5.8 8.3 1 6.7 6.1 1.25 — 5.2 Porosity (%) NaCl/CPC ratioImmersion temperatue (° C.) by weight 37 60 0 33.3 37.3 0.25 46.1 41.90.5 49.4 54.3 0.75 56.1 59.4 1 — 64.2 1.25 63.9 67.9

EXAMPLE 9 Effect of NaCl Content and Heat Treatment on C.S.

The procedures of EXAMPLE 1 were repeated except that NaCl was used toreplace KCl, the paste was immersed in the immersing liquid (deionizedwater at 37° C.) for 7 days, and NaCl/CPC ratio by weight was set inTable 9. Further. The resulting porous CPC block was heat treated. Theheat treatment included heating the porous CPC block in a furnance atthe temperature set in Table 9 for 1 hr with a heating rate of 10°C./min. The compressive strength was measured after cooling of theheated CPC block. The conditions and results are listed in Table 9.TABLE 9 Dry compressive strength (MPa) Heat treatment NaCl/CPC ratio byweight temperatue (° C.) 0.25 0.5 Without heat treatment 28.8 11.2 5038.8 16.1 100 36.8 21.0 200 46.1 29.5 350 54.5 30.0 400 39.4 29.5 45036.6 18.3

In the other preferred embodiments of the present invention Na₂CO₃ wasused as the pore-forming powder in the preparation of the porous CPCblocks, which had the dry compressive strength and the porositycomparable to those disclosed in Examples 1-9.

Although the present invention has been described with reference tospecific details of certain embodiments thereof, it is not intended thatsuch details should be regarded as limitations upon the scope of theinvention except as and to the extent that they are included in theaccompanying claims. Many modifications and variations are possible inlight of the above disclosure.

1-37. (canceled)
 38. A method of forming a porous calcium phosphatearticle comprising: adding a paste to a mold, wherein the pastecomprises at least one calcium phosphate compound combined with at leastone pore forming powder and at least one setting agent; subjecting thepaste to a molding pressure of greater than 1 MPa to form a hardenedcalcium phosphate article; immersing the hardened calcium phosphatearticle in one or more liquids to form the porous calcium phosphatearticle.
 39. The method of claim 38, further comprising applying heat tothe paste before or while the molding pressure is applied to the paste.40. The method of claim 38, further comprising subjecting the porouscalcium phosphate article to one or more heat treatments, wherein thetemperature of the heat treatments is about 100° C. to about 800° C. 41.The method of claim 38, wherein the calcium phosphate compound isselected from the group consisting of alpha-tricalcium phosphate(α-TCP), beta-tricalcium phosphate (β-TCP), tetracalcium phosphate(TTCP), monocalcium phosphate monohydrate (MCPM), monocalcium phosphateanhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalciumphosphate anhydrous (DCPA), octacalcium phosphate (OCP), calciumdihydrogen phosphate, calcium dihydrogen phosphate hydrate, acid calciumpyrophosphate, anhydrous calcium hydrogen phosphate, calcium hydrogenphosphate hydrate, calcium pyrophosphate, calcium triphosphate, calciumphosphate tribasic, calcium polyphosphate, calcium metaphosphate,anhydrous tricalcium phosphate, tricalcium phosphate hydrate, andamorphous calcium phosphate.
 42. The method of claim 38, wherein thecalcium phosphate compound comprises at least one calcium phosphateparticulate compound having calcium phosphate whiskers on the surface ofthe particles, wherein said calcium phosphate whiskers have a length ofabout 1-5000 nm and a width of about 1-500 nm.
 43. The method of claim38, wherein the pore forming powder is at least partially water-soluble.44. The method of claim 38, wherein the pore forming powder comprises aninorganic salt.
 45. The method of claim 38, wherein the pore formingpowder comprises an organic salt.
 46. The method of claim 38, whereinthe pore forming powder is selected from the list consisting of LiCl,KCl, NaCl, MgCl₂, CaCl₂, NaIO₃, KI, Na₃PO₄, K₃PO₄, Na₂CO₃, aminoacid-sodium salt, amino acid-potassium salt, glucose, polysaccharide,fatty acid-sodium salt, fatty acid-potassium salt, potassium bitartrate(KHC₄H₄O₆), potassium carbonate, potassium gluconate (KC₆H₁₁O₇),potassium-sodium tartrate (KNaC₄H₄O₆.4H₂O), potassium sulfate (K₂SO₄),sodium sulfate, and sodium lactate.
 47. The method of claim 38, whereinthe weight ratio of pore forming powder-to-calcium phosphate compound isfrom about to 0.25 to about 3.0.
 48. The method of claim 38, wherein thesetting agent comprises an acidic solution, a basic solution, orsubstantially pure water.
 49. The method of claim 48, wherein saidacidic solution is selected from the group consisting of nitric acid(HNO₃), hydrochloric acid (HCl), phosphoric acid (H₃PO₄), carbonic acid(H₂CO₃), sodium dihydrogen phosphate (NaH₂PO₄), sodium dihydrogenphosphate monohydrate (NaH₂PO₄.H₂O), sodium dihydrogen phosphatedihydrate, sodium dihydrogen phosphate dehydrate, potassium dihydrogenphosphate (KH₂PO₄), ammonium dihydrogen.phosphate (NH₄H₂PO₄), malicacid, acetic acid, lactic acid, citric acid, malonic acid, succinicacid, glutaric acid, tartaric acid, oxalic acid and mixtures thereof.50. The method of claim 48, wherein said basic solution is selected fromthe group consisting of ammonia, ammonium hydroxide, alkali metalhydroxide, alkali earth hydroxide, disodium hydrogen phosphate(Na₂HPO₄), disodium hydrogen phosphate dodecahydrate, disodium hydrogenphosphate heptahydrate, sodium phosphate dodecahydrate (Na₃PO₄.12H₂O),dipotassium hydrogen phosphate (K₂HPO₄), potassium hydrogen phosphatetrihydrate (K₂HPO₄.3H₂O), potassium phosphate tribasic (K₃PO₄),diammonium hydrogen phosphate ((NH₄)₂HPO₄), ammonium phosphatetrihydrate ((NH₄)₃PO₄.3H₂O), sodium hydrogen carbonate (NaHCO₃), sodiumcarbonate Na₂CO₃, and mixtures thereof.
 51. The method of claim 38,wherein applying the molding pressure further comprises reducing theliquid-to-powder ratio of the paste.
 52. The method of claim 38, whereinthe article is adapted for use as a medical impant.
 53. The method ofclaim 38, wherein the one or more liquids comprise a basic solution, anacidic solution, a solution of substantially physiological pH, anorganic solvent, or substantially pure water.
 54. The method of claim38, wherein at least one of the liquids comprises a solution of HCl, asolution of (NH₄)₂HPO₄, or Hank's solution.
 55. The method of claim 38,wherein at least one of the liquids comprises at least one source ofcalcium and at least one source of phosphate.
 56. The method of claim38, wherein the hardened calcium phosphate article is immersed in one ormore liquids for a period of time sufficient to remove at least aportion of the pore forming powder from the calcium phosphate article.57. The method of claim 38, wherein the hardened calcium phosphatearticle is immersed in at least one liquid for at least 24 hours. 58.The method of claim 38, wherein the paste further comprises livingcells.
 59. The method of claim 38, wherein at least one of the liquidsfurther comprises living cells.